RNA processing mechanisms control lymphocyte development and activation

RNA加工机制控制淋巴细胞的发育和激活

• 批准号: BB/J001457/1
• 负责人: Christopher Smith
• 金额: $ 8.17万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ001457%2F1
• 关键词: RNA; processing; mechanisms; control; lymphocyte

One of the well recognised features of ageing is an increased susceptibility to infection that is caused by a decline in the function of the immune system. Our immune system forms during foetal development and the early neonatal period and is made up of many types of cells including the white blood cells. These are continuously replenished throughout the life-course from specialised stem cells called haematopoietic stem cells that are found in the bone marrow. The white blood cells can be further divided into lymphocytes and non lymphocytes. Amongst the lymphocytes are B cells which produce antibodies and specialised cells that kill virally infected cells. A class of lymphocyte that develops in an organ called the thymus is called the T cell and this cell co-ordinates the function of antibody producing and killer lymphocytes. One important feature of lymphocytes is that they hold a memory of previous encounters with infections. This has been used to create vaccines which make us immune to diseases without having to suffer the disease. While vaccines work well in young individuals they work poorly, or not at all, in the elderly. Because of the importance of lymphocytes they have been much studied and we have plenty of information on the different stages of development the cells go through as they mature and become stimulated by encounter with antigen (the technical term immunologists use for anything that stimulates the immune system). We know much about the signalling processes that take place inside the cell when receptors on the surface of lymphocytes are triggered. We also know much about a class of genes that encode proteins, called transcription factors, which act as on/off switches for genes in the DNA. Transcription factors convert the information encoded in the DNA sequence of genes into a message, called mRNA, which specifies the order in which amino acids are incorporated into proteins. Our project is aimed at understanding how the mRNA is regulated subsequent to its production. We suspect special proteins, called mRNA binding proteins, physically interact with the mRNA and control how long it remains in the cell and the rate at which it can give rise to new proteins. This type of regulation is called post-transcriptional control and is far less well understood. Our study will ask what the function of these mRNA binding proteins is in lymphocytes and will reveal how they work. Our gaol is to understand how mRNA binding proteins interact with signalling pathways and ultimately with transcription factors to control lymphocytes and the immune response.

衰老的一个公认特征是免疫系统功能下降导致的感染易感性增加。我们的免疫系统在胎儿发育和新生儿早期形成，由多种类型的细胞组成，包括白色血细胞。这些细胞在整个生命过程中不断从骨髓中发现的称为造血干细胞的专门干细胞中补充。白色血细胞可进一步分为淋巴细胞和非淋巴细胞。淋巴细胞中有产生抗体的B细胞和杀死病毒感染细胞的特化细胞。一类淋巴细胞在一个叫做胸腺的器官中发育，称为T细胞，这种细胞协调抗体产生和杀伤淋巴细胞的功能。淋巴细胞的一个重要特征是它们对以前遇到的感染有记忆。这被用来制造疫苗，使我们对疾病免疫，而不必遭受疾病。虽然疫苗在年轻人身上效果很好，但在老年人身上效果很差，或者根本不起作用。由于淋巴细胞的重要性，人们对它们进行了大量研究，并且我们掌握了大量有关细胞成熟并因遇到抗原而受到刺激（免疫学家使用的技术术语，指任何刺激免疫系统的物质）时所经历的不同发育阶段的信息。当淋巴细胞表面的受体被触发时，我们对细胞内发生的信号传导过程了解很多。我们也知道很多关于一类编码蛋白质的基因，称为转录因子，它们充当DNA中基因的开关。转录因子将基因的DNA序列中编码的信息转化为称为mRNA的信息，该信息指定氨基酸并入蛋白质的顺序。我们的项目旨在了解mRNA在其产生后如何调节。我们怀疑有一种特殊的蛋白质，称为mRNA结合蛋白，与mRNA发生物理相互作用，并控制mRNA在细胞中停留的时间以及产生新蛋白质的速度。这种类型的调控被称为转录后控制，目前还不太清楚。我们的研究将询问这些mRNA结合蛋白在淋巴细胞中的功能，并揭示它们是如何工作的。我们的目标是了解mRNA结合蛋白如何与信号通路相互作用，并最终与转录因子相互作用，以控制淋巴细胞和免疫反应。

项目成果

Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells.

• DOI: 10.1038/s41467-017-00454-2
• 发表时间: 2017-09-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Díaz-Muñoz MD;Kiselev VY;Le Novère N;Curk T;Ule J;Turner M
• 通讯作者: Turner M

The RNA-binding protein HuR is essential for the B cell antibody response.

• DOI: 10.1038/ni.3115
• 发表时间: 2015-04
• 期刊: Nature immunology
• 影响因子: 30.5

Polypyrimidine tract binding protein 1 regulates the activation of mouse CD8 T cells.

• DOI: 10.1002/eji.202149781
• 发表时间: 2022-07
• 期刊: European journal of immunology
• 影响因子: 5.4

Intron retention as a component of regulated gene expression programs.

• DOI: 10.1007/s00439-017-1791-x
• 发表时间: 2017-09
• 期刊: Human genetics
• 影响因子: 5.3
• 作者: Jacob AG;Smith CWJ
• 通讯作者: Smith CWJ

Intron retention as a component of regulated gene expression programs

内含子保留作为调控基因表达程序的一个组成部分

• DOI: 10.17863/cam.11024
• 发表时间: 2017
• 作者: Jacob A